After picking up just one point, the Swiss can no longer make the top two and will be automatically demoted if they fail to win in Zurich, while their opponents still harbour hopes of making the UEFA Nations League's knockout phase.
Match preview
Having twice let a lead slip at home to Denmark in their most recent outing, Switzerland saw their aim of reaching this season's Nations League quarter-finals thwarted - and the wait for a first win since Euro 2024 went on.
Murat Yakin's side went ahead two times in St Gallen - through Remo Freuler's opener and a Zeki Amdouni penalty just before half time - but they ultimately had to settle for a point, which is their only one so far in Group 4.
Previously, Die Nati had lost away to the Danes, followed by defeats against Spain and Serbia in October, so they are in acute danger of slipping into League B as the group stage reaches its finale.
Their task is quite simple, as anything other than victory on Friday night would seal demotion; winning will bring their survival fight down to the last matchday, as finishing third would secure a playoff against second-tier opponents.
Even then, reigning European and Nations League champions Spain await in Switzerland's final fixture, which will take place in Tenerife next Monday.
A divisive figure whose waning reputation was restored at the Euros, Yakin will be keen to avoid writing a relegation on his CV, as he hopes to stay put in the hotseat and lead his country towards the 2026 World Cup.
Serbia may have failed to make it out of their group at Euro 2024, while the Swiss strode through to the quarter-finals, but they have enjoyed a more positive Nations League campaign thus far.
Dragan Stojkovic led his squad to a commendable goalless draw against Spain on the opening matchday, before overseeing a 2-0 defeat in Denmark and last month's home win over Switzerland - the latter being sealed by an Aleksandar Mitrovic strike on the hour mark.
Although the Eagles were utterly dominated in their return fixture against La Roja, losing 3-0 in Cordoba after having just one-third of the ball, they can still seek a place in the newly expanded knockout phase.
Three points behind second-placed Denmark, victory at Zurich's Stadion Letzigrund would take the race into next week's final round; however, Serbia will be unable to go through if they lose and Denmark avoid defeat - or if they draw and the Danes beat Spain.
Such is the nature of UEFA's new format, they could yet be relegated by letting Switzerland surpass them, or by finishing third and then losing a playoff.
Switzerland Nations League form:
L
L
L
D
Switzerland form (all competitions):
W
L
L
L
L
D
Serbia Nations League form:
D
L
W
L
Serbia form (all competitions):
D
D
D
L
W
L
Team News
Facing a severe selection headache in defence, Murat Yakin must do without Fabian Schar - who retired from international football after the Euros - Nico Elvedi and Manuel Akanji, with the latter missing this month's action due to an adductor injury.
For the first time in eight years, none of the trio will be in Switzerland's starting lineup, meaning the only centre-backs in a 24-man squad are uncapped pair Aurele Amenda and Albian Hajdari.
Midfielder Eray Comert may be asked to drop into the hosts' back line, as versatile veteran Denis Zakaria is also sidelined, in addition to Bologna winger Dan Ndoye.
While Granit Xhaka will captain Die Nati from midfield, Serbia's skipper is all-time top scorer Aleksandar Mitrovic, who has found the net 59 times in 96 appearances for his country and has been in fine form with Saudi Pro League giants Al-Hilal.
Another Saudi-based star, Sergej Milinkovic-Savic has been left out, while his brother, goalkeeper Vanja Milinkovic-Savic, withdrew.
The latter's Torino teammate Ivan Ilic is ruled out by a knee injury sustained during the recent Derby della Mole against Juventus, but Dragan Stojkovic can at least welcome back Juve striker Dusan Vlahovic, who was unavailable in October.
Switzerland possible starting lineup:
Kobel; Widmer, Hajdari, Comert, Rodriguez; Freuler, Xhaka; Amdouni, Rieder, Aebischer; Embolo
Serbia possible starting lineup:
Petrovic; Erakovic, Milenkovic, Pavlovic; Nedeljkovic, Maksimovic, Grujic, Terzic; Samardzic; Vlahovic, Mitrovic
We say: Switzerland 2-2 Serbia
Though Switzerland defeated Serbia at both of the last two World Cups, they lost when these nations most recently met and are enduring an injury crisis.